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897
Multistep organic synthesis ofmodular photosystemsNaomi Sakai* and Stefan Matile*
Review Open Access
Address:Department of Organic Chemistry, University of Geneva, Geneva,Switzerland
Email:Naomi Sakai* - [email protected];Stefan Matile* - [email protected]
* Corresponding author
Keywords:asparagusic acid; charge-transfer cascades; chromophores; disulfideexchange; hydrazone exchange; molecular switches;naphthalenediimides; π-stacks; surface-initiated polymerization
Beilstein J. Org. Chem. 2012, 8, 897–904.doi:10.3762/bjoc.8.102
Received: 18 February 2012Accepted: 09 May 2012Published: 19 June 2012
This article is part of the Thematic Series "Molecular switches and cages".
Guest Editor: D. Trauner
© 2012 Sakai and Matile; licensee Beilstein-Institut.License and terms: see end of document.
AbstractQuite extensive synthetic achievements vanish in the online supporting information of publications on functional systems. Underap-
preciated, their value is recognized by experts only. As an example, we here focus in on the recent synthesis of multicomponent
photosystems with antiparallel charge-transfer cascades in co-axial hole- and electron-transporting channels. The synthetic steps are
described one-by-one, starting with commercial starting materials and moving on to key intermediates, such as asparagusic acid, an
intriguing natural product, as well as diphosphonate “feet”, and panchromatic naphthalenediimides (NDIs), to finally reach the
target molecules. These products are initiators and propagators for self-organizing surface-initiated polymerization (SOSIP), a new
method introduced to secure facile access to complex architectures. Chemoorthogonal to the ring-opening disulfide exchange used
for SOSIP, hydrazone exchange is then introduced to achieve stack exchange, which is a “switching” technology invented to drill
giant holes into SOSIP architectures and fill them with functional π-stacks of free choice.
897
IntroductionThe architecture of photosystem 1 is rather sophisticated,
probably as sophisticated as it gets with photosystems today
(Figure 1) [1]. It is composed of three co-axial π-stacks that are
grown from an indium tin oxide (ITO) surface. With lower
frontier molecular orbital (FMO) levels, the “yellow” stacks can
transport photogenerated electrons toward the ITO surface
along the gradient in their LUMO. With higher FMO levels, the
“red” stacks can transport holes along the gradient in their
HOMOs in the opposite direction, away from the ITO surface.
The double-channel architecture 1 with antiparallel redox
gradients has been referred to as OMARG-SHJ, that is supra-
Beilstein J. Org. Chem. 2012, 8, 897–904.
898
Scheme 1: Synthesis of initiator 2.
Figure 1: Schematic structure of photosystem 1 on indium tin oxide(ITO, grey) with antiparallel gradients in hole (p, h+) and electron(n, e−) transporting coaxial channels. HOMO (solid) and LUMO levels(dashed) of all components (color coded) are indicated in eV againstvacuum (−5.1 eV for Fc/Fc+), including triethanolamine (TEOA), usedas mobile hole transporter.
molecular n/p-heterojunctions with oriented multicomponent/
color antiparallel redox gradients [2,3]. With n/p contact areas
maximized down to the molecular level, photoinduced charge
separation (i.e., charge generation) should be as favorable as
directional charge translocation (i.e., charge separation) along
redox gradients in the molecular channels. With photosystem 1,
these high expectations could finally be tested experimentally
[1]. OMARG-SHJs turned out to be best quantified with bimol-
ecular charge recombination efficiencies ηBR, that is, losses in
photonic energy. Photosystem 1 gave ηBR = 22%; gradient-free
controls gave ηBR = 50%; destructive gradients gave ηBR =
76%. These results are very satisfactory. They also confirmed
that significant synthetic efforts to build sophisticated func-
tional architectures can be worthwhile. In the original commu-
nication, these synthetic efforts completely disappeared in the
online supporting information [1]. The fact that results on syn-
thesis are self-explanatory to all and do not require much
discussion can be considered as a marvelous illustration of the
success of the field. However, to illustrate the frequent lack of
appreciation of the synthetic organic chemistry in work on func-
tional systems, the total synthesis of photosystem 1 will be
described step-by-step in the following.
Results and DiscussionSynthesis of initiatorsPhotosystem 1 is constructed from the molecular building
blocks 2–6 (Schemes 1-3). Initiator 2 is composed of a central
naphthalenediimide (NDI) [4-19] to act as a template for the
central stack and two peripheral NDIs to act as templates for
stack exchange. They are embedded into hydrogen-bonded
networks, to assure self-organization, and four geminal diphos-
phonates [20,21] for tetravalent anchoring on the ITO surface.
Beilstein J. Org. Chem. 2012, 8, 897–904.
899
Scheme 2: Synthesis of propagators 3 and 4.
The geminal diphosphonates 7 were synthesized from meth-
ylene bis(phosphonic dichloride) 8 (Scheme 1) [20,21]. Conver-
sion with benzyl alcohol and pyridine as a base yielded tetra-
benzyl methylene bisphosphonate 9. Activation with sodium
hydride and alkylation with ethyl bromoacetate (10) gave ethyl
ester 11, and final ester hydrolysis lead to the desired acid 7.
The peripheral NDIs 12, designed to template for stack
exchange on initiator 2, were prepared from naphthalenedianhy-
dride (NDA) 13. Microwave-assisted imidation [15] with the
two amines 14 and 15 at 140 °C gave the mixed diimide 16 in
excellent 66% yield together with the symmetric diimide side
products. Amines were liberated by palladium-catalyzed Alloc
removal and reacted with acid 7. The obtained amide 17 was
deprotected with acid to afford the desired aldehyde 12.
The central NDI 18 of initiator 2, designed to initiate and
template for SOSIP, was accessible from NDA 13 as well. The
synthesis of NDI 19 by microwave-assisted imidation with Boc-
protected lysine 20 has been reported before in the literature
[15]. Reaction with Cbz-hydrazine gave the Cbz-protected NDI
hydrazide 21. After chemoselective, acid-catalyzed deprotec-
tion, the liberated amines were coupled with the Boc-protected
cysteine tert-butyl disulfide 22. The obtained amide 23 was
treated with TFA for Boc removal and coupled with the geminal
diphosphonate foot 7. Deprotection of both hydrazides and
diphosphonates in NDI 24 gave 18, which was reacted in situ
with NDI 12 to yield initiator 2.
Synthesis of propagatorsThe synthesis of propagator 3 starts with NDA 13 as well
(Scheme 2). Diimidation with Cbz-protected lysine 25 gave the
diacid 26. Activation with EDC, HOBt and TEA was followed
by the reaction with tert-butyl carbazate under mild conditions.
The protected hydrazide 27 was obtained in 59% yield over two
steps. The Cbz protecting groups were removed chemoselec-
tively by hydrogenolysis over Pd–C in the presence of acetic
acid, and the obtained diamine was reacted with the activated
asparagusic acid 28. Hydrazide deprotection in NDI 29 and in
situ hydrazone formation with benzaldehyde 30 gave propa-
gator 3.
In contrast to propagator 3, propagator 4 is constructed around a
yellow, core-substituted cNDI fluorophore. Nevertheless, the
synthesis of this target molecule also starts with NDA 13. Bro-
mination in the core with dibromocyanuric acid (31) afforded
an intractable mixture containing the 2,6-dibromo NDA 32
together with lower and higher homologues [16]. However,
pure product 33 could be readily isolated from this mixture after
transformation of the NDAs into the core-substituted naph-
thalenetetraesters (cNTEs). Nucleophilic core-substitution with
ethanolate gave cNTE 34 as described in the literature [16].
NTE 34 was subjected to basic ester hydrolysis followed by
diimidation with lysine 25. From this point, the synthesis of
cNDI propagator 4 was analogous to the synthesis of NDI prop-
agator 3. Reaction of EDC-activated diacid 35 with tert-butyl
Beilstein J. Org. Chem. 2012, 8, 897–904.
900
Scheme 3: Synthesis of stack exchangers 5 and 6. Compounds 5, 6,45 and 47 are mixtures of 2,6- and 3,7-regioisomers.
carbazate followed by deprotection of the obtained cNDI 36 and
coupling with activated asparagusic acid 28 gave cNDI 37.
Hydrazide deprotection quenched by benzaldehyde 30 gave the
yellow cNDI propagator 4.
The activated asparagusic acid 28 was prepared by following
literature procedures [22-25]. In the first step from bis(hydroxy-
methyl)malonate 38, simple nucleophilic substitution is coupled
with an ester hydrolysis and a debrominative decarboxylation.
Another nucleophilic substitution with thioacetate converted
bromide 39 into thioester 40. Addition of a second thioacetate
gave dithioester 41, which was hydrolyzed with a base. Oxi-
dation of dithiol 42 with molecular oxygen gave asparagusic
acid (43), which is the natural product that contributes to the
characteristic odor of asparagus. Activation with NHS gave the
ester 28, ready for coupling with amines, such as 27 or 36.
Synthesis of stack exchangersThe synthesis of the red cNDIs 5 and 6 for stack exchange was
possible in very few steps starting from available synthetic
intermediates (Scheme 3). cNDI 5, with one bromo and one
alkylamino substituent in the core, was prepared from crude
dibromo cNDA 32. Microwave-assisted reaction [15] with
amines 14 and 15 gave the mixed cNDI 44 together with the
symmetric side products. The obtained mixture of 2,6- and 3,7-
regioisomers was not separated throughout the entire synthesis
of photosystem 1. Nucleophilic aromatic substitution with
isopropylamine for 10 min at room temperature gave the red
cNDI 45, which was followed by deprotection with acid to give
the target aldehyde 5.
The more pinkish cNDI 6 was synthesized from the cNTE 34
following the procedure developed for cNDI 5. Diimide forma-
tion with amines 14 and 15 followed by core substitution of the
mixed cNDI 46 and deprotection of the red cNDI 47 gave the
desired aldehyde 6.
Self-organizing surface-initiated polymeriza-tionWith the five building blocks 2–6 in hand, the solid-phase syn-
thesis of photosystem 1 on ITO surfaces could be launched.
ITO was first cleaned with RCA solution, that is, a boiling 5:1:1
mixture of water, 24% NH4OH and 30% H2O2, and then rinsed
with bidistilled water and EtOH, and dried. Then the ITO was
immersed in a 3 mM solution of initiator 2 in DMSO for 2 days.
The formation of monolayers of 48 on ITO electrodes was fol-
lowed by the inhibition of potassium ferricyanide reduction in
solution, and by absorption spectroscopy (Scheme 4). The
obtained monolayers of 48 were annealed for 1 h in the oven at
120 °C. These conditions are known to improve the covalent
bonding between phosphonic acids and the ITO substrate [26].
The disulfide protecting groups on the surface of monolayer 48
were removed with DTT to afford free thiols on the surface of
monolayer 49. For SOSIP [18,19], the concentration of propa-
gators had to be optimized to a critical SOSIP concentration,
cSOSIP. Below cSOSIP, ring-opening disulfide-exchange poly-
merization [27] does not occur, whereas above cSOSIP, the poly-
merization occurs everywhere, not only on the surface but also
in solution. To determine cSOSIP, ITO plates with and without
activated initiators were incubated together in the same solu-
tion of propagators. The amount of polymers either grown from
the ITO surface or deposited on the ITO surface by precipita-
tion during polymerization in solution was determined by
absorption spectroscopy. Plots of the absorption of the elec-
trode as a function of the concentration of the propagator in
solution revealed both cSOSIP, the critical concentration needed
for SOSIP, and cSOL, the critical concentration needed for poly-
merization in solution. Operational SOSIP was demonstrated
with cSOSIP < cSOL, and failure of SOSIP with cSOSIP = cSOL.
Both cSOSIP and cSOL depended strongly on the conditions, i.e.,
the concentration and nature of the base catalyst, the nature of
initiator and propagator, the temperature, the presence of
oxygen in the solution and, most importantly, the composition
of the solvent mixture used.
For propagator 3, cSOSIP = 3.5 mM was found in a 1:1 mixture
of chloroform and methanol with 100 mM DIPEA as a base
catalyst. Incubation of monolayer 49 in this solution gave
Beilstein J. Org. Chem. 2012, 8, 897–904.
901
Scheme 4: Synthesis of photosystem 1, self-organizing surface-initiated polymerization (SOSIP). R1 = SH (50) or oxidized derivative (51), greysurface = ITO. Dotted lines from diphosphonate groups indicate the bonds to the ITO surface. The polymer structures are generalized and idealizedstructures, which are consistent with the experimental results. They will naturally contain defects.
SOSIP architecture 50. To add the yellow stacks in photo-
system 1, photosystem 50 was incubated with propagator 4 at
cSOSIP = 7 mM in chloroform/methanol (1:1) with 100 mM
DIPEA. The obtained oriented diblock disulfide polymers 51
were characterized by the absorption of colorless NDIs at
385 nm and the absorption of yellow cNDIs at 470 nm.
Assuming regular growth, these absorptions provided a mean-
ingful approximation of the average composition n and m of the
poly(disulfide) [27].
Stack exchangeStack exchange within the resulting SOSIP photosystem 51
was initiated with excess hydroxylamine (Scheme 5). The
chemoorthogonality of disulfide and hydrazone exchange has
been demonstrated previously by several groups [28-31].
Benzaldehyde removal as oxime was followed by HPLC. The
hydrazide-rich pores produced in the resulting architecture 52
were first filled by reversible covalent capture of the red cNDI
aldehyde 5.
Stack exchange was easily detectable by comparison of the
respective maxima in the absorption spectra. Exchange of the
benzaldehyde hydrazones in photosystem 51 with NDIs
occurred with an excellent 75–95% yield. Moreover, the yield
of stack exchange was nearly independent of the thickness of
the photosystem. Control experiments revealed that in the case
of initiators without extra NDI templates, the yield drops to
40% for thin photosystems and further decreases with
increasing thickness to an irrelevant 25%. This significant
difference demonstrates the central importance of templated
synthesis for successful stack exchange.
To engineer antiparallel gradients into the red stack of photo-
system 53, partial stack exchange was envisioned. A part of the
red cNDI stack, l, was removed by brief treatment with hydrox-
ylamine. The produced, shallower holes in photosystem 54 were
filled with cNDI aldehyde 6. The desired photosystem 1 with
antiparallel redox gradients in coaxial hole- and electron-trans-
porting channels was obtained.
Beilstein J. Org. Chem. 2012, 8, 897–904.
902
Scheme 5: Synthesis of photosystem 1, stack exchange. R1 = SH or oxidized derivative, R1 = CH2CHCH2. 5 and 6 are mixtures of 2,6- and 3,7-regioisomers.
Graphical summary of complex transforma-tionsBoth SOSIP and post-SOSIP stack exchange can be quite
complicated to follow in complete molecular structures
(Scheme 4 and Scheme 5). We thus summarize both processes
in schematic form (Scheme 6). To recapitulate briefly from this
perspective, we repeat that the solid-phase synthesis begins with
the deposition of initiator 2 on ITO. Activation of monolayer 48
with DTT produces monolayer 49 with free thiols on the
surface. Recognition of propagators 3 on the surface of 49
places the strained disulfides of asparagusic acid right on top of
the activated thiolates on the surface. Covalent capture by ring-
opening disulfide exchange generates new thiolates on the
surface of the growing photosystem 55 for continuing SOSIP.
The obtained ladderphane 50 is then treated with propagator 4.
Ring-opening disulfide exchange SOSIP via intermediates 56
leads to photosystem 51 with a two-component redox gradient
in the π-stack.
Post-SOSIP stack exchange is then initiated by benzaldehyde
removal as oxime 57. The giant pores drilled into photosystem
52 are first filled completely with red cNDI 5. Subsequently, the
partial removal of the new stack in photosystem 53 as oxime 58
and covalent capture of 6 in the more shallow pores in photo-
system 54 affords the desired double-gradient photosystem 1.
ConclusionThe objective of this brief highlight was to exemplify the syn-
thetic efforts that are often hidden behind short papers on func-
tional systems. Quite extensive multistep synthesis has been
covered, followed by innovative surface-initiated polymeriza-
tion and chemoorthogonal dynamic covalent chemistry. The
excellent properties obtained confirm that significant synthetic
efforts to build more sophisticated functional systems can be
justified and rewarding. In this research, multistep organic syn-
thesis is the means rather than the end. Therefore, the main
difference from research dedicated to synthetic methodology is
Beilstein J. Org. Chem. 2012, 8, 897–904.
903
Scheme 6: Schematic overview over SOSIP and stack exchange.
that the individual steps often remain unoptimized as long as the
level reached is sufficient to produce large enough amounts of
the target molecule without extensive effort and cost. However,
the quality, timeliness and beauty of the transformations
employed are the same, as is the pleasure of occasional contri-
butions to improve or innovate in the field of organic synthesis.
AcknowledgementsWe thank the University of Geneva, the European Research
Council (ERC Advanced Investigator), the National Centre of
Competence in Research (NCCR) Chemical Biology and the
Swiss NSF for financial support.
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